Christine Brefel-Courbon

Effect of levodopa on pain threshold in Parkinson's disease: A clinical and positron emission tomography study

Patients suffering from Parkinsons disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H215O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain‐induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain‐induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain‐induced activation in nociceptive pathways, which can be reduced by levodopa.

Limitations of current Parkinson's disease therapy.

Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinsons disease in the early stages of the disease. However, once the “honeymoon” period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from “dopa‐resistant” motor symptoms (speech impairment, abnormal posture, gait and balance problems), “dopa‐resistant” nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug‐related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety. Ann Neurol 2003;53 (suppl 3):S3–S15

Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease

Dyskinesia is a frequent and disabling side effect in patients with Parkinsons disease treated with chronic dopatherapy. Preclinical data in the 1‐methyl‐4‐phenyl‐1,2,3,6,‐tetrahydropyridine (MPTP) monkey suggest that alpha‐2 antagonists may reduce dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia. We assessed, in a pilot randomised placebo‐controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha‐2 antagonist, on motor parkinsonian disability and L‐DOPA‐induced dyskinesia following an acute oral challenge of L‐DOPA in 18 patients with Parkinsons disease. The severity of L‐DOPA‐induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L‐DOPA. These results suggest that blocking alpha‐2 receptors in patients with Parkinsons disease might improve L‐DOPA‐induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long‐term management of dyskinetic patients with Parkinsons disease.

Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy

We conducted a randomized, double‐blind, placebo‐controlled, single‐patient (N = 1) trial to evaluate the efficacy of zolpidem in a 48‐year‐old woman with an akinetic mutism. Motor and cognitive examinations and functional imaging were performed. Acute administration of zolpidem markedly improved motor performance and neuropsychological status. Cerebral metabolism (18F‐fluorodeoxyglucose positron emission tomography) increased in postrolandic territories and in frontal cortex. Using the H215O positron emission tomography, we found a drug‐induced activation in the anterior cingulate and orbitofrontal cortices. Zolpidem induced a transient improvement in motor and cognitive performances. This paradoxical effect could result from an activation of limbic loops modulating motivational processes. Ann Neurol 2007

Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

α-Synuclein Gene Rearrangements in Dominantly Inherited Parkinsonism: Frequency, Phenotype, and Mechanisms

OBJECTIVE Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism. DESIGN Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California). SUBJECTS Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened. RESULTS Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement. CONCLUSIONS Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.

Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study.

A prospective survey was performed to characterize the prevalence of sleep attacks and to evaluate precipitating factors in a group of 236 patients with idiopathic Parkinsons disease. Sleep attacks were reported by 72 patients (30.5%). Multivariate analysis showed a marked association between the occurrence of sudden sleep episodes and first autonomic failure, followed by treatment with ropinirole and bromocriptine. The present work underlines the major contributing role of autonomic failure followed by dopamine agonists in the occurrence of such an event. Because a relationship between sleep attacks and not only ropinirole but also bromocriptine treatment was described, the present work suggests that sleep attacks are a common side effect of all dopamine agonists.

α2-Adrenoceptor Antagonists

Postmortem studies have shown that noradrenergic neurotransmission is impaired in Parkinson’s disease. This abnormality may have functional importance because (α2-adrenoceptor antagonists, which increase central noradrenergic transmission, improve motor behaviour in various animal models of this disease.Pilot clinical data suggest that (α2-antagonists may indeed have several potential indications in the treatment of Parkinson’s disease: (i) 3 recent placebocontrolled studies reported an improvement in motor scores following short term intravenous or long term oral administration of two different (α2-antagonists (idazoxan and efaroxan), suggesting that both drugs provide symptomatic benefit with regard to motor symptoms, especially rigidity and akinesia; (ii) an acute oral challenge with idazoxan reduced the severity of ‘peak-dose’ levodopa-induced dyskinesia, one of the most disabling complications of long term therapy with that drug, in a placebo-controlled study; (iii) biochemical and pharmacological experiments have suggested that levodopa-resistant parkinsonian symptoms, such as frozen gait, cognitive dysfunction, depressive state and dysautonomia, could be improved by enhancing central noradrenergic function; however, controlled clinical studies are necessary to evaluate the usefulness of (α2-adrenoceptor antagonists in these indications; and (iv) some preliminary experimental data support the hypothesis that noradrenergic mechanisms could be involved in the progression of Parkinson’s disease; thus, there is a rationale for testing the putative neuroprotective effects of (α2-adrenoceptor antagonists in this disorder.It has yet to be determined whether the antiparkisonian effects of (α2-antagonists are due to a direct effect of noradrenaline (norepinephrine) on motor systems or to an indirect effect, by means of noradrenergic interactions with dopamine or other neurotransmitters controlling motor behaviour or via other mechanisms.A careful evaluation of (α2-antagonists in the treatment of Parkinson’s disease must also consider their potential adverse effects, because these drugs possess cardiovascular and psychiatric properties which might compromise their risk-benefit ratio.

Does ageing influence deep brain stimulation outcomes in Parkinson's disease?

We sought to define the influence of ageing in clinical, cognitive, and quality‐of‐life outcomes after subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinsons disease (PD). We performed motor assessment (UPDRS), mood tests, cognitive, and quality of life evaluation (PDQ‐39) on PD patients before surgery, and 12 and 24 months after, and we recorded adverse events. The variations of these parameters after surgery were correlated with age using regression statistical tests. Cerebral bleeding risk was evaluated by a nonparametric test. We enrolled 45 patients (mean age 60 ± 9 years, range 40–73). No significant correlation was found between age and motor scores and PDQ‐39 improvements at 12 months. At 24 months, there was a significant negative correlation between age and the improvement of three dimensions of PDQ 39 (mobility, activities of daily life, and cognition). Cognitive impairment showed no correlation, but apathy and depression were positively correlated with age. Significant statistical difference was observed between cerebral bleeding and age. STN‐DBS is an effective treatment for elderly patients with advanced PD. A longer follow‐up duration and a larger population seem necessary to better assess the quality of life perception in elderly patients and to determinate the real risk of hemorrage.

Sleep disruption, daytime somnolence and ‘sleep attacks’ in Parkinson's disease: a clinical survey in PD patients and age-matched healthy volunteers

Recent case reports of ‘sleep attacks’ (SA) in patients with Parkinsons disease (PD) generated concerns about drug‐induced daytime somnolence in this population. However, there are nearly no comparative data on sleep and vigilance problems between PD patients and normal controls. We performed a cross‐sectional survey in PD patients and age‐matched controls using a structured questionnaire on PD history, treatments, co‐morbidity, activities of daily living, habits, exercise, sleep pattern, driving, pre‐existing nocturnal problems, daytime somnolence, episodes of SA and the circumstances in which such episodes occurred. Daytime somnolence was also measured with the Epworth Sleepiness Scale (ESS) and sleep quality with the Pittsburgh Sleep Quality Index (PSQI). 176 PD patients and 174 controls were included. The same proportion of PD patients (27%) and controls (32%) reported episodes of SA, but these were more frequent in PD patients and occurred more frequently during situations requiring attention (10.8% vs. 1.7%, p<10−3). More PD patients had abnormal daytime somnolence (ESS) and poor sleeping quality (PSQI). The most consistent factor associated with SA was the duration of levodopa therapy and the predictive value of an abnormal ESS score was rather poor (40.7%). Abnormal daytime somnolence and poor sleep quality at night are more frequent in PD patients than in normals. However, SA are reported in both groups, although less frequently in the normals during activities that requires attention.